Phase I study evaluating KIN-3248, a next-generation, irreversible pan-FGFR inhibitor, in patients with advanced cholangiocarcinoma, urothelial carcinoma and other solid tumors harboring FGFR2 and/or FGFR3 gene alterations
Annals of Oncology(2023)
Abstract
Preclinical and clinical evidence indicates that activating FGFR1-4 gene alterations drives oncogenesis and tumor growth. Pharmacological inhibition of FGFR1-4 leads to tumor shrinkage and disease control, supporting development of FGFR inhibitors. A critical limitation of currently approved, clinical-stage FGFRi is the emergence of secondary, on-target resistance mutations (mutn) that reduce duration of response. About 70% of cholangiocarcinoma (CCA) patients treated with FGFRi exhibit secondary FGFR2 kinase domain resistance mutn at the time of relapse. KIN-3248 is a next-generation, selective, irreversible, small molecule pan-FGFRi, designed to inhibit primary FGFR oncogenic alterations as well as secondary kinase domain mutn associated with disease progression. Preclinically, KIN-3248 has favorable pharmaceutical properties, is well-tolerated with continuous, daily oral administration in GLP toxicology studies and is efficacious against primary FGFR2 and FGFR3 oncogenic driver alterations as well as secondary FGFR2 resistance mutn (eg, gatekeeper and molecular brake) in human cancer cells and PDX models. KN-4802 (NCT05242822) is a first in human, multicenter, Ph1 study of KIN-3248 in pts with advanced and metastatic solid tumors (AMST) harboring FGFR2 and/or FGFR3 gene alterations. KIN-3248 is given continuously in 28-day cycles until drug intolerance or disease progression. The study is conducted in 2 parts: Part A is a dose escalation of KIN-3248 to MTD/RP2D. Part B evaluates a selected dose of KIN-3248 in previously treated intrahepatic cholangiocarcinoma (ICC) or urothelial carcinoma (UC), treatment naïve ICC or UC, or other AMST. Enrollment criteria include ECOG PS 0-1 and prior standard treatment with clinical benefit, if appropriate. Primary endpoints are safety and preliminary antitumor activity. Secondary objectives include pharmacokinetic and pharmacodynamic assessments including measures of FGFR pathway modulation. Planned sample size is 140 pts and the study is enrolling patients in the US, EU and globally. NCT05242822. Kinnate Biopharma Inc. Kinnate Biopharma Inc.
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Key words
fgfr2,advanced cholangiocarcinoma,urothelial cholangiocarcinoma,other solid tumors,next-generation,pan-fgfr
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